Based on the growing awareness that mutagenesis plays an important role in two important diseases, cancer and atherosclerosis (the major cause of heart attack), the research proposed in this grant will undertake the task of elucidating the mechanism of mutagenesis in human and mammalian cells. We propose to isolate DNA repair deficient mutants by BrdU - black light and lethal incorporation methods, and use them to analyze the genetic control of DNA repair and mutagenesis. Our studies with the phorbol ester indicate that the tumor promoter can modify the expression of induced mutations. We will test whether cyclic AMP is involved in this epigenetic mechanism. Furthermore, we propose to develop a screening system to determine whether a carcinogen is a mutagen or gene modulator, using the combined ouabain and 6-thioguanine resistant mutation systems.